CA2100503C - Piperidine derivatives of benzimidazole - Google Patents
Piperidine derivatives of benzimidazoleInfo
- Publication number
- CA2100503C CA2100503C CA002100503A CA2100503A CA2100503C CA 2100503 C CA2100503 C CA 2100503C CA 002100503 A CA002100503 A CA 002100503A CA 2100503 A CA2100503 A CA 2100503A CA 2100503 C CA2100503 C CA 2100503C
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- Prior art keywords
- benzimidazole
- piperidine
- dimethylethyl
- phenyl
- ethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
New piperidine derivatives of benzimidazole of the formula:
(see fig. I) wherein n is 1 or 2 and R is lower alkyl, lower alkenyl or lower cycloalkyl, or a pharmaceutically acceptable salt thereof, are useful antihistaminic and antiallergic agents.
(see fig. I) wherein n is 1 or 2 and R is lower alkyl, lower alkenyl or lower cycloalkyl, or a pharmaceutically acceptable salt thereof, are useful antihistaminic and antiallergic agents.
Description
NEW PIPERIDINE DERIVATIVES OF BENZIMIDAZOLE
DESCRIPTION OF THE INVENTION
The search for effective drugs for the treatment of allergic diseases has experienced a great development in the last few years due to an increase in the frequency these phenomena occur, especially in the developed world, as well as to the lack of truly effective drugs that do not produce side effects.
Allergic diseases are characterized by the release of mediators from the inside of certain cells of the organism, being histamine one of the most important released mediators.
Products antagonizing histamine action have been found to be the most useful for the treatment of illnesses of allergic type although most of them have effects on the central nervous system (CNS). Obtaining new antihistamine compounds devoid of effects on the CNS is one of the top priorities of the pharmaceutical industry.
This invention refers to new piperidine derivatives of benzimidazole with a high level of antihistaminic and antiallergic activity and a low toxicity. These compounds are represented by formula I, wherein n is 1 or 2 and R is a lower alkyl, lower alkenkyl or lower cycloalkyl, such as methyl, ethyl, isopropyl, cyclopropyl and vinyl, as well as the pharmaceutically acceptable acid addition salts thereof.
CA 02100~03 1998-04-07 N -(CH2~ ~ ~ Me O-R
Compounds I may be conveniently prepared by means of a N-alkylation reaction of a N-unsubstituted benzimidazole represented by the general formula II with an ~ N--(CH2~ Me alkylating agent of the type Y-CH2-CH2-0-R', where Y is a good leaving group, in the presence of an inorganic base such as a carbonate, a bicarbonate or a hybride of an alkaline metal.
The new piperidinbenzimidazoles thus obtained may be transformed into the corresponding salts by treating them in ethanolic solutions with pharmaceutically acceptable acids, such as hydrochloric, hydrobromic, phosphoric, oxalic, propanoic, butanedioic and similar acids.
CA 02100~03 1998-04-07 The following examples illustrate, without limitation, the specific methods employed in production of a representative number of compounds embraced by this invention.
Preparation of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)-piperidine-4-yl]-1-(2-methoxyethyl)-lH-benzimidizaole 1.73 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)-methyl)piperidine-4-yl]-lH-benzimidazole are dissolved in 15 milliliters of dimethylformamide under a nitrogen atmosphere and 0.24 g of 40% sodium hydride oil solution are added; the resulting suspension is stirred at room temperature for two hours and then 0.47 ml. of 2-chloroethyl-methyl ether are added; the reaction mixture is heated at 60~ for six hours and then it is poured onto water and extracted with ether (3 x 30 ml); the ethereal phase is washed with water (3 x 20 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 2.3 g of an oil. The residue is converted into the hydrogen fumarate salt in ethanolic solution. The salt is filtered off and dried yielding 0.9 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-1-(2-methoxyethyl)-lH-benzimidazole, hydrogen-fumarate.
CA 02100~03 1998-04-07 Mp: 133-116~ (d).
IR (KBs), ~ (cm~1): 640, 1100, 1460, 1505, 2500-3500.
H RMN (CC14) ~ : 1,2 (s, 9H, 3CH3), 1,5-2,4 (m, 4H, piperidine), 2,4-3,2 (m, 5H, piperidine), 3,1(S, 3H, O CH3), 3,4 (s, 2H, N-CH2-Ph), 3,3-3,6 (t, 2H, CH2 CH2O), 3,9-4,2 (t, 2H, N-CH2-CH2), 6,7-7,6 (m, 8H, Ar).
Preparation of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)-piperidine-4-yl]-1-(2-ethoxyethyl)-lH-benzimidazole To a solution of 3.47 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-lH-benzimidazole in 80 ml of acetonitrile, 1.38 g of potassium carbonate and 1.08 ml of 2-chloroethyl-ethyl ether are added and the mixture is refluxed for 8 hours; then is left to cool and poured onto 200 ml of water; it is extracted with ether (3 x 30 ml) and the ethereal layer is washed with water (3 x 20 ml) and dried over anhydrous sodium sulfate. The oil obtained by elimination of the ether is purified by column chromatography by using chloroform/methanol (98/2) as eluent, thus obtaining 2 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-1-(2-ethoxyethyl)-lH-benzimidazole. Mp: 51-53~C.
CA 02100~03 1998-04-07 - 5a -IR (KBr), ~ (cm~1): 750, 1120, 1460, 1505, 2980.
H RMN (CCl4) ~: 0,7-l,o (t, 3H, CH2CH3), 1,1 (s, 9H, 3CH3), 1,4-2,1 (m, 4H, piperidine), 2,2-3,0 (m, 5H, piperidine), 2,9-3,3 (q, 2H, CH2-CH3), 3,2 (s, 2H, CH2-Ph), 3,2-3,5 (t, 2H, CH2-CH2-O), 3,8-4,2 (t, 2H, N-CH2CH2), 6,7-7,5 (m, 8H, Ar).
The product is transformed into the corresponding hydrogen fumarate (Mp: 161-163~ d) by treatment in ethanol with 0.55 g of fumaric acid.
Preparation of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)-piperidine-4-yl]-1-[(2-(1-methylethoxy)ethyl)]-lH-benzimidazole To a solution of 2.94 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-lH-benzimidazole in 50 ml of dimethylformamide, 2.17 g of 2-[1-(methylethoxy)-ethyl]tosylate and 0.45 g of sodium hydrogen carbonate are added at room temperature; the resulting suspension is stirred at room temperature for four hours and then concentrated. The residue is taken up in water and extracted with ether. The ethereal extracts were washed with water (2 x 20 ml) and dried over anhydrous sodium sulfate; after concentration they give CA 02100~03 1998-04-07 - 5b -an oil which is transformed into the hydrogen fumarate salt in ethanolic solution. The salt is filtered off and dried yielding 1.5 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)-methyl)piperidine-4-yl]-1-(methylethoxy)ethyl)-lH-benzimidazole hydrogen fumarate.
Mp: 210-212~C.
IR (KBr) (free base), ~ cm~1: 755, 1100, 1120, 1460, 1505, 2980.
1H RMN (CCl4) (free base) ~: 0,5-0.7 [(d, 6H CH(CH3)2], 0,9 (s, 9H, 3CH3), 1,3-2,0 (m, 4H, piperidine), 2,2-2,9 (m, 5H, piperidine), 2,9-3,2 (m, lH
' l 1 ' 2100~03 CH), 3,1 (s, 2H, CH2-Ph), 3,1-3,4 (t, 2H, CH2CH20), 3,7-4,0 (t, 2H, N CH2CH2), 6,7-7,5 (m, 8H Ar).
Preparation of 2-[1-(2-(4-(1,1-dimethylethyl)-phenyl)ethyl) piperidin-4-yl3-1-t2-(1-methylethoxy)ethyl]-lH-benzimidazole 10 To a suspension of 3.61 g of 2-~1-(2-(4-(1,1-dimethylethyl) phenyl)ethyl)piperidin-4-yl]-lH-benzimidazole in 40 ml of DMF, 0.48 g of a sodium hydride suspension in oil are added; it is stirred at room temperature for 1 hour and then a solution of 2.58 g of 2-[1-(methylethoxy)ethyl] tosylate in 20 ml of DMF
15 are slowly added. The mixture is heated at 60 ~C for 20 hours, poured onto water and extracted with ether; the ethereal layer is dried over anhydrous sodium sulfate and the solvent evaporated; the residue is purified by column chromatography y i e 1 d i n g 2 5 g o f 2 - [ 1 - (2 - (4 - ( 1 , 1 -20 dimethylethyl)phenyl)ethyl)piperidine-4-yl~-1-[2-(1-methylethoxy)ethyl)-lH-benzimidazole.
Mp: 115-117 ~C.
RMN (DCC13) ~ : 1,0-1,1 [d, 6H, CH-(CH3)2], 1,3 (s, sH, 3CH3), 1,75-2,3 (m, 6H, piperidine), 2,6-2,75 (m, 2H, CH2), 2,75-2,9 (m, 2H, CH2), 2,95-3,1 (m, lH, CH), 3,1-3,25 (m, 2H, piperidine), 3,65-3,75 (t, 2H, CH20), 4,25-4,35 (t, 2H, CH2 N), 7,1-7,2 (m, ~H, Ar), 7,7-7,8 (m, lH, Ar) Preparation of 2-tl-(2-(4-(1,1-dimethylethyl)-phenyl)ethyl) piperidin-4-yl]-l-(2-ethoxyethy~ H-benzimidazole /'~ 2100~03 1.5 g of a sodium hydride suspension in oil are added to another suspension of 10.83 g of 2-[1-(2-(4-(1,1-dimethylethyl)phenyl)ethyl)piperidin-4-yl]-lH-benzimidazolein lS0 ml of dimethylformamide and the mixture is stirred for 1 5 hour at room temperature, heated at 60 ~C for 16 hours, poured onto water and extracted with ether. The extracts are washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained oil is purified by column chromatography yielding 6 g of 1-(2-ethoxyethyl) -2-~1-(2-(4-10 (1, l-dimethylethyl) phenyl) ethyl) piperidine-4 -yl] -lH-benzimidazole.
Mp: 138--140~C
IR (KBr), ~, cm 1 740, 1120, 1235, 1450 y 1500 cm 1.
15 RMN (DCC13) ~: 1,07-1,15 (t, 3H, CH2CH3), 1,28 (s, 9H, 3CH3), 1,95-2,3 (m, 6H, piperidine), 2,6-2,75 (m, 2H, CH2), 2,75-2,9 (m, 2H, CH2), 2,95-3,05 (m, lH, CH), 3,15-3,25 (m, 2H, piperidine), 3,30-3,45 (q, 2H, CH2 CH3), 3,65-3,75 (t, 2H, CH20), 4,25-4,35 (t, 2H, CH2N), 7,15-7,35 (m, 7H, Ar), 7,7-7,8 (m, lH, Ar).
Antihistaminic and antiallergic properties of the compounds were evaluated in vitro and in vivo.
H1-antihistaminic activity in vitro: Histamine-induced contractions of isolated guinea-pig ileum.
Distal ileum was obtained from male albino guinea pig (300-30 500 g). All animals were fasted overnight and killed by cervical dislocation and then exsanguinated. Segments approximately 20 cm long, were excised 5 cm above the ileocecal junction and fragments 25 mm long were suspended in a 20 ml organ bath in Tyrode solution (pH: 7.4), maintained at 37 ~C
3S and aerated with carbogen (95g6 ~2 and 5% co2). The tissue was washed by upward displacement of the bathing fluid. With an effective 1.2 g loading tension, the ileum was kept for 45 min 1- (stabilization period). An accumulative dose-response curve for ! histamine was isotonically recorded with increasing 5 concentrations and the tissue, after washing with Tyrode solution, was allowed to equilibrate. Twenty minutes later a second concentration-response curve was obtained previous addition of different concentrations of antagonist drugs. The results were calculated from the concentration-response curves 10 for histamine at each drug concentration. All the concentrations were tested 2 to 4 times. Based on the type of antagonism observed, the PA2 or PD~2 were calculated (Magnus, Pflugers, Arch. Ges. Physiol. 102, 123 (1904); Arunlakshana, o. and ~child, MØ, Brit. J. Pharma. 14, 48 (1959); Van Rossum 15 J.M., Arch. Int. Pharmacodyn. 143, 3-4, 299 (1963)). In table I the obtained results are shown.
TABLE
In vitro antihistaminic activity of compounds of general formula I.
Substituents n R pD~2 (n) 1 CH3 6.75 (2) 1 CH2CH3 7.08 (4) (CH3)2 7.30 (4) 2 CH(CH3)2 7.00 (4) 2 CH2CH3 7.52 (4) Astemizole 7.00 (4) Terfenadine 6.33 (5) CA 02100~03 1998-04-07 g H1-antihistaminic activity in vivo: Vascular permeability increase induced by histamine in rats.
Female Wistar rats (120-150 g) were used. They were fasted for 18 hours prior to the assay. Each product was administered orally at doses of 1 mg/kg (5 mg/kg when R1 is a methyl group), and 1 hour later 50 ~l of 0.01~ (w/v) histamine solution were injected intradermally on both sides of the middle dorsal line of the rat; immediately after the histamine injection, 4 ml/kg of 0.625~ Evan's blue solution in PSS were injected iv. 30 min after the dye injection, animals were sacrificed and the skin was removed. The extravasated dye sites were extracted with formamide and the dye spectrophotometrically evaluated. (Lefevbre P., Salmon J., Lecomte J. and Cauwenberge Van H., C.R. Soc. Biol. 156, 183 (1962); Udaka K. Takeuchi Y. and Movat H.Z., Proc. Soc. Exp.
Biol. Med. 133, 1384 (1970). Inhibition (~) of the histamine-induced vascular permeability increase was calculated vs a control group. The obtained results are shown in Table II.
Antiallergic activity in vivo: Vascular permeability increase induced by 48 hours homologous passive cutaneous anaphylaxis (PCA) in rats.
Female Wistar rats (120-150 g) were used. They were sensitized passively by intradermic injections of homologous ovoalbium antiserum on both sides of the middle shaved-back line of the rat. Forty-eight hours later each test compound CA 02100~03 1998-04-07 - 9a -was administered orally at doses of 1 mg/kg (5 mg/kg when Rl is a methyl group) and 1 h later PCA reaction was induced by iv injection of Evan's blue solution and ovoalbium in PSS
solution. The animals were sacrificed 30 minutes after the dye injection and the skin was removed. The extravasated dye sites were extracted with formamide and the dye spectrophotometrically evaluated. (Mota, I. Life Sciences 12, ~_' 21005~3 917 (1963); Mota, I. Immunology 7, 681 (1964). The inhibition (%) of the PCA-induced vascular permeability increase was calculated vs a control group. The obtained results are shown in Table II.
TABLE II
Inhibition of the increase of vascular permeability of 10 compounds of general formula I.
Substituents Increase Increase by Histamine by P.C.A.
n R ~ ~
1CH(CH3)2 50 40 2CH(CH3)2 25 30 Astemizole 50 38 Terfenadine 20 37 A preliminary study similar to Irwins's test in mice was 35 carried out at doses of 100 and 300 mg/kg at 1, 2, 3, 4 and 24 hours after the treatment. As reference ketotifene was used.
The results are summarized in Tables III and IV.
,1 ~ 2100~3 Tabla III Effects on CNS of compounds of general formula I at doses of 100 mg/kg.
-100 mg/kg S Affected animals / Total animalsa Substituents n RDeath Sponta Palpe- Hypo- Con- Loss Loss neous bral ther- vul- of of Acti- Ptosis mia sions right- pin-vity time neal decrea reflex reflex se 1 CH3 - 3/4 ~ 2/4 1 CH2CH3 - - - - - - _ 1 CH(CH3)2 ~ ~ - - - _ _ Ketotlfene a If no effects were detected, no figures are shown.
Tabla IV Effects on CNS of compounds of general formula I at doses of 300 mg/kg.
300 mg/kg Affected animals / Total animalsa Substituents 35 n R Death Sponta Palpe- Hypo- Con- Loss Loss neous bral ther- vul- of of Acti- Ptosis mia sions right- pin-vity time neal decrea reflex reflex se 1 CH3 4/4 4/4 4/4 4/4 4/4 4/4 4t4 1 CH~CH3 - 4/4 ~ ~ 4/4 1 CH~CH3)2 - - - _ 2 CH2CH3 - _ _ - - _ _ H2CH3 2/4 - - - - _ Ketotlfene - 2/41/4 1/4 - 1/4 a If no effects were detected, no figures are shown.
CA 02100~03 1998-04-07 In view of their antihistaminic properties, compounds of formula I and their acid addition salts are very useful in the treatment of allergic diseases such as allergic rhinitis, ailergic conjunctivitis, chronic urticaria, allergic asthma and the like.
The compounds described in this invention may be formulated into various pharmaceutical forms for administration purposes. To prepare the antiallergic compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example to aid solubility, may be added. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
DESCRIPTION OF THE INVENTION
The search for effective drugs for the treatment of allergic diseases has experienced a great development in the last few years due to an increase in the frequency these phenomena occur, especially in the developed world, as well as to the lack of truly effective drugs that do not produce side effects.
Allergic diseases are characterized by the release of mediators from the inside of certain cells of the organism, being histamine one of the most important released mediators.
Products antagonizing histamine action have been found to be the most useful for the treatment of illnesses of allergic type although most of them have effects on the central nervous system (CNS). Obtaining new antihistamine compounds devoid of effects on the CNS is one of the top priorities of the pharmaceutical industry.
This invention refers to new piperidine derivatives of benzimidazole with a high level of antihistaminic and antiallergic activity and a low toxicity. These compounds are represented by formula I, wherein n is 1 or 2 and R is a lower alkyl, lower alkenkyl or lower cycloalkyl, such as methyl, ethyl, isopropyl, cyclopropyl and vinyl, as well as the pharmaceutically acceptable acid addition salts thereof.
CA 02100~03 1998-04-07 N -(CH2~ ~ ~ Me O-R
Compounds I may be conveniently prepared by means of a N-alkylation reaction of a N-unsubstituted benzimidazole represented by the general formula II with an ~ N--(CH2~ Me alkylating agent of the type Y-CH2-CH2-0-R', where Y is a good leaving group, in the presence of an inorganic base such as a carbonate, a bicarbonate or a hybride of an alkaline metal.
The new piperidinbenzimidazoles thus obtained may be transformed into the corresponding salts by treating them in ethanolic solutions with pharmaceutically acceptable acids, such as hydrochloric, hydrobromic, phosphoric, oxalic, propanoic, butanedioic and similar acids.
CA 02100~03 1998-04-07 The following examples illustrate, without limitation, the specific methods employed in production of a representative number of compounds embraced by this invention.
Preparation of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)-piperidine-4-yl]-1-(2-methoxyethyl)-lH-benzimidizaole 1.73 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)-methyl)piperidine-4-yl]-lH-benzimidazole are dissolved in 15 milliliters of dimethylformamide under a nitrogen atmosphere and 0.24 g of 40% sodium hydride oil solution are added; the resulting suspension is stirred at room temperature for two hours and then 0.47 ml. of 2-chloroethyl-methyl ether are added; the reaction mixture is heated at 60~ for six hours and then it is poured onto water and extracted with ether (3 x 30 ml); the ethereal phase is washed with water (3 x 20 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 2.3 g of an oil. The residue is converted into the hydrogen fumarate salt in ethanolic solution. The salt is filtered off and dried yielding 0.9 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-1-(2-methoxyethyl)-lH-benzimidazole, hydrogen-fumarate.
CA 02100~03 1998-04-07 Mp: 133-116~ (d).
IR (KBs), ~ (cm~1): 640, 1100, 1460, 1505, 2500-3500.
H RMN (CC14) ~ : 1,2 (s, 9H, 3CH3), 1,5-2,4 (m, 4H, piperidine), 2,4-3,2 (m, 5H, piperidine), 3,1(S, 3H, O CH3), 3,4 (s, 2H, N-CH2-Ph), 3,3-3,6 (t, 2H, CH2 CH2O), 3,9-4,2 (t, 2H, N-CH2-CH2), 6,7-7,6 (m, 8H, Ar).
Preparation of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)-piperidine-4-yl]-1-(2-ethoxyethyl)-lH-benzimidazole To a solution of 3.47 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-lH-benzimidazole in 80 ml of acetonitrile, 1.38 g of potassium carbonate and 1.08 ml of 2-chloroethyl-ethyl ether are added and the mixture is refluxed for 8 hours; then is left to cool and poured onto 200 ml of water; it is extracted with ether (3 x 30 ml) and the ethereal layer is washed with water (3 x 20 ml) and dried over anhydrous sodium sulfate. The oil obtained by elimination of the ether is purified by column chromatography by using chloroform/methanol (98/2) as eluent, thus obtaining 2 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-1-(2-ethoxyethyl)-lH-benzimidazole. Mp: 51-53~C.
CA 02100~03 1998-04-07 - 5a -IR (KBr), ~ (cm~1): 750, 1120, 1460, 1505, 2980.
H RMN (CCl4) ~: 0,7-l,o (t, 3H, CH2CH3), 1,1 (s, 9H, 3CH3), 1,4-2,1 (m, 4H, piperidine), 2,2-3,0 (m, 5H, piperidine), 2,9-3,3 (q, 2H, CH2-CH3), 3,2 (s, 2H, CH2-Ph), 3,2-3,5 (t, 2H, CH2-CH2-O), 3,8-4,2 (t, 2H, N-CH2CH2), 6,7-7,5 (m, 8H, Ar).
The product is transformed into the corresponding hydrogen fumarate (Mp: 161-163~ d) by treatment in ethanol with 0.55 g of fumaric acid.
Preparation of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)-piperidine-4-yl]-1-[(2-(1-methylethoxy)ethyl)]-lH-benzimidazole To a solution of 2.94 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-lH-benzimidazole in 50 ml of dimethylformamide, 2.17 g of 2-[1-(methylethoxy)-ethyl]tosylate and 0.45 g of sodium hydrogen carbonate are added at room temperature; the resulting suspension is stirred at room temperature for four hours and then concentrated. The residue is taken up in water and extracted with ether. The ethereal extracts were washed with water (2 x 20 ml) and dried over anhydrous sodium sulfate; after concentration they give CA 02100~03 1998-04-07 - 5b -an oil which is transformed into the hydrogen fumarate salt in ethanolic solution. The salt is filtered off and dried yielding 1.5 g of 2-[1-((4-(1,1-dimethylethyl)phenyl)-methyl)piperidine-4-yl]-1-(methylethoxy)ethyl)-lH-benzimidazole hydrogen fumarate.
Mp: 210-212~C.
IR (KBr) (free base), ~ cm~1: 755, 1100, 1120, 1460, 1505, 2980.
1H RMN (CCl4) (free base) ~: 0,5-0.7 [(d, 6H CH(CH3)2], 0,9 (s, 9H, 3CH3), 1,3-2,0 (m, 4H, piperidine), 2,2-2,9 (m, 5H, piperidine), 2,9-3,2 (m, lH
' l 1 ' 2100~03 CH), 3,1 (s, 2H, CH2-Ph), 3,1-3,4 (t, 2H, CH2CH20), 3,7-4,0 (t, 2H, N CH2CH2), 6,7-7,5 (m, 8H Ar).
Preparation of 2-[1-(2-(4-(1,1-dimethylethyl)-phenyl)ethyl) piperidin-4-yl3-1-t2-(1-methylethoxy)ethyl]-lH-benzimidazole 10 To a suspension of 3.61 g of 2-~1-(2-(4-(1,1-dimethylethyl) phenyl)ethyl)piperidin-4-yl]-lH-benzimidazole in 40 ml of DMF, 0.48 g of a sodium hydride suspension in oil are added; it is stirred at room temperature for 1 hour and then a solution of 2.58 g of 2-[1-(methylethoxy)ethyl] tosylate in 20 ml of DMF
15 are slowly added. The mixture is heated at 60 ~C for 20 hours, poured onto water and extracted with ether; the ethereal layer is dried over anhydrous sodium sulfate and the solvent evaporated; the residue is purified by column chromatography y i e 1 d i n g 2 5 g o f 2 - [ 1 - (2 - (4 - ( 1 , 1 -20 dimethylethyl)phenyl)ethyl)piperidine-4-yl~-1-[2-(1-methylethoxy)ethyl)-lH-benzimidazole.
Mp: 115-117 ~C.
RMN (DCC13) ~ : 1,0-1,1 [d, 6H, CH-(CH3)2], 1,3 (s, sH, 3CH3), 1,75-2,3 (m, 6H, piperidine), 2,6-2,75 (m, 2H, CH2), 2,75-2,9 (m, 2H, CH2), 2,95-3,1 (m, lH, CH), 3,1-3,25 (m, 2H, piperidine), 3,65-3,75 (t, 2H, CH20), 4,25-4,35 (t, 2H, CH2 N), 7,1-7,2 (m, ~H, Ar), 7,7-7,8 (m, lH, Ar) Preparation of 2-tl-(2-(4-(1,1-dimethylethyl)-phenyl)ethyl) piperidin-4-yl]-l-(2-ethoxyethy~ H-benzimidazole /'~ 2100~03 1.5 g of a sodium hydride suspension in oil are added to another suspension of 10.83 g of 2-[1-(2-(4-(1,1-dimethylethyl)phenyl)ethyl)piperidin-4-yl]-lH-benzimidazolein lS0 ml of dimethylformamide and the mixture is stirred for 1 5 hour at room temperature, heated at 60 ~C for 16 hours, poured onto water and extracted with ether. The extracts are washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained oil is purified by column chromatography yielding 6 g of 1-(2-ethoxyethyl) -2-~1-(2-(4-10 (1, l-dimethylethyl) phenyl) ethyl) piperidine-4 -yl] -lH-benzimidazole.
Mp: 138--140~C
IR (KBr), ~, cm 1 740, 1120, 1235, 1450 y 1500 cm 1.
15 RMN (DCC13) ~: 1,07-1,15 (t, 3H, CH2CH3), 1,28 (s, 9H, 3CH3), 1,95-2,3 (m, 6H, piperidine), 2,6-2,75 (m, 2H, CH2), 2,75-2,9 (m, 2H, CH2), 2,95-3,05 (m, lH, CH), 3,15-3,25 (m, 2H, piperidine), 3,30-3,45 (q, 2H, CH2 CH3), 3,65-3,75 (t, 2H, CH20), 4,25-4,35 (t, 2H, CH2N), 7,15-7,35 (m, 7H, Ar), 7,7-7,8 (m, lH, Ar).
Antihistaminic and antiallergic properties of the compounds were evaluated in vitro and in vivo.
H1-antihistaminic activity in vitro: Histamine-induced contractions of isolated guinea-pig ileum.
Distal ileum was obtained from male albino guinea pig (300-30 500 g). All animals were fasted overnight and killed by cervical dislocation and then exsanguinated. Segments approximately 20 cm long, were excised 5 cm above the ileocecal junction and fragments 25 mm long were suspended in a 20 ml organ bath in Tyrode solution (pH: 7.4), maintained at 37 ~C
3S and aerated with carbogen (95g6 ~2 and 5% co2). The tissue was washed by upward displacement of the bathing fluid. With an effective 1.2 g loading tension, the ileum was kept for 45 min 1- (stabilization period). An accumulative dose-response curve for ! histamine was isotonically recorded with increasing 5 concentrations and the tissue, after washing with Tyrode solution, was allowed to equilibrate. Twenty minutes later a second concentration-response curve was obtained previous addition of different concentrations of antagonist drugs. The results were calculated from the concentration-response curves 10 for histamine at each drug concentration. All the concentrations were tested 2 to 4 times. Based on the type of antagonism observed, the PA2 or PD~2 were calculated (Magnus, Pflugers, Arch. Ges. Physiol. 102, 123 (1904); Arunlakshana, o. and ~child, MØ, Brit. J. Pharma. 14, 48 (1959); Van Rossum 15 J.M., Arch. Int. Pharmacodyn. 143, 3-4, 299 (1963)). In table I the obtained results are shown.
TABLE
In vitro antihistaminic activity of compounds of general formula I.
Substituents n R pD~2 (n) 1 CH3 6.75 (2) 1 CH2CH3 7.08 (4) (CH3)2 7.30 (4) 2 CH(CH3)2 7.00 (4) 2 CH2CH3 7.52 (4) Astemizole 7.00 (4) Terfenadine 6.33 (5) CA 02100~03 1998-04-07 g H1-antihistaminic activity in vivo: Vascular permeability increase induced by histamine in rats.
Female Wistar rats (120-150 g) were used. They were fasted for 18 hours prior to the assay. Each product was administered orally at doses of 1 mg/kg (5 mg/kg when R1 is a methyl group), and 1 hour later 50 ~l of 0.01~ (w/v) histamine solution were injected intradermally on both sides of the middle dorsal line of the rat; immediately after the histamine injection, 4 ml/kg of 0.625~ Evan's blue solution in PSS were injected iv. 30 min after the dye injection, animals were sacrificed and the skin was removed. The extravasated dye sites were extracted with formamide and the dye spectrophotometrically evaluated. (Lefevbre P., Salmon J., Lecomte J. and Cauwenberge Van H., C.R. Soc. Biol. 156, 183 (1962); Udaka K. Takeuchi Y. and Movat H.Z., Proc. Soc. Exp.
Biol. Med. 133, 1384 (1970). Inhibition (~) of the histamine-induced vascular permeability increase was calculated vs a control group. The obtained results are shown in Table II.
Antiallergic activity in vivo: Vascular permeability increase induced by 48 hours homologous passive cutaneous anaphylaxis (PCA) in rats.
Female Wistar rats (120-150 g) were used. They were sensitized passively by intradermic injections of homologous ovoalbium antiserum on both sides of the middle shaved-back line of the rat. Forty-eight hours later each test compound CA 02100~03 1998-04-07 - 9a -was administered orally at doses of 1 mg/kg (5 mg/kg when Rl is a methyl group) and 1 h later PCA reaction was induced by iv injection of Evan's blue solution and ovoalbium in PSS
solution. The animals were sacrificed 30 minutes after the dye injection and the skin was removed. The extravasated dye sites were extracted with formamide and the dye spectrophotometrically evaluated. (Mota, I. Life Sciences 12, ~_' 21005~3 917 (1963); Mota, I. Immunology 7, 681 (1964). The inhibition (%) of the PCA-induced vascular permeability increase was calculated vs a control group. The obtained results are shown in Table II.
TABLE II
Inhibition of the increase of vascular permeability of 10 compounds of general formula I.
Substituents Increase Increase by Histamine by P.C.A.
n R ~ ~
1CH(CH3)2 50 40 2CH(CH3)2 25 30 Astemizole 50 38 Terfenadine 20 37 A preliminary study similar to Irwins's test in mice was 35 carried out at doses of 100 and 300 mg/kg at 1, 2, 3, 4 and 24 hours after the treatment. As reference ketotifene was used.
The results are summarized in Tables III and IV.
,1 ~ 2100~3 Tabla III Effects on CNS of compounds of general formula I at doses of 100 mg/kg.
-100 mg/kg S Affected animals / Total animalsa Substituents n RDeath Sponta Palpe- Hypo- Con- Loss Loss neous bral ther- vul- of of Acti- Ptosis mia sions right- pin-vity time neal decrea reflex reflex se 1 CH3 - 3/4 ~ 2/4 1 CH2CH3 - - - - - - _ 1 CH(CH3)2 ~ ~ - - - _ _ Ketotlfene a If no effects were detected, no figures are shown.
Tabla IV Effects on CNS of compounds of general formula I at doses of 300 mg/kg.
300 mg/kg Affected animals / Total animalsa Substituents 35 n R Death Sponta Palpe- Hypo- Con- Loss Loss neous bral ther- vul- of of Acti- Ptosis mia sions right- pin-vity time neal decrea reflex reflex se 1 CH3 4/4 4/4 4/4 4/4 4/4 4/4 4t4 1 CH~CH3 - 4/4 ~ ~ 4/4 1 CH~CH3)2 - - - _ 2 CH2CH3 - _ _ - - _ _ H2CH3 2/4 - - - - _ Ketotlfene - 2/41/4 1/4 - 1/4 a If no effects were detected, no figures are shown.
CA 02100~03 1998-04-07 In view of their antihistaminic properties, compounds of formula I and their acid addition salts are very useful in the treatment of allergic diseases such as allergic rhinitis, ailergic conjunctivitis, chronic urticaria, allergic asthma and the like.
The compounds described in this invention may be formulated into various pharmaceutical forms for administration purposes. To prepare the antiallergic compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example to aid solubility, may be added. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
Claims (8)
1. A compound of the formula and the pharmaceutically acceptable salts thereof, wherein n is 1 or 2 and R is lower alkyl, lower alkenyl or lower cycloalkyl.
2. A compound according to claim 1, consisting of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-1-(2-methoxyethyl)-1H-benzimidazole and the pharmaceutically acceptable salts thereof.
3. A compound according to claim 1, consisting of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-1-(2-ethoxyethyl)-1H-benzimidazole and pharmaceutically acceptable salts thereof.
4. A compound according to claim 1, consisting of 2-[1-((4-(1,1-dimethylethyl)phenyl)methyl)piperidine-4-yl]-1-[2-(1-(methylethoxy)ethyl)]-1H-benzimidazole and the pharmaceutically acceptable salts thereof.
5. A compound according to claim 1, consisting of 2-[1-(2-(4-(1,1-dimethylethyl)phenyl)ethyl)piperidine-4-yl]-1-[2-(1-methylethoxy)ethyl)]-1H-benzimidazole and the pharmaceutically acceptable salts thereof.
6. A compound according to claim 1, consisting of 2-[1-(2-(4-(1,1-dimethylethyl)phenyl)ethyl)piperidine-4-yl]-1-(2-ethoxyethyl)-1H-benzimidazole and the pharmaceutically acceptable salts thereof.
7. An antihistaminic and antiallergic pharmaceutical composition comprising an inert carrier material and an effective amount of a compound from the group claimed in any of the claims 1 to 6.
8. Use of a compound according to any one of claims 1 to 6 as an antihistaminic or antiallergic agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES09201512A ES2048109B1 (en) | 1992-07-20 | 1992-07-20 | PROCEDURE FOR THE PREPARATION OF NEW PIPERIDIC DERIVATIVES OF BENCIMIDAZOLE. |
| ES9201512 | 1992-07-20 |
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| Publication Number | Publication Date |
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| CA2100503A1 CA2100503A1 (en) | 1994-01-21 |
| CA2100503C true CA2100503C (en) | 1998-09-29 |
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| CA002100503A Expired - Fee Related CA2100503C (en) | 1992-07-20 | 1993-07-14 | Piperidine derivatives of benzimidazole |
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| US (1) | US5322850A (en) |
| EP (1) | EP0580541B1 (en) |
| JP (1) | JPH07291964A (en) |
| KR (1) | KR940005609A (en) |
| AT (1) | ATE185344T1 (en) |
| AU (1) | AU667920B2 (en) |
| CA (1) | CA2100503C (en) |
| DE (1) | DE69326650T2 (en) |
| ES (1) | ES2048109B1 (en) |
| FI (1) | FI933213A (en) |
| MX (1) | MX9304215A (en) |
| NO (1) | NO303014B1 (en) |
| TW (1) | TW225529B (en) |
| ZA (1) | ZA935195B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2097317C (en) * | 1990-12-14 | 2002-02-12 | Albert A. Carr | Antiallergic piperdinyl benzimidazoles |
| MX9701305A (en) | 1994-08-25 | 1998-05-31 | Merrell Pharma Inc | Novel substituted piperidines useful for the treatment of allergic diseases. |
| US6211199B1 (en) | 1995-11-17 | 2001-04-03 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases |
| US6423704B2 (en) | 1995-12-20 | 2002-07-23 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases |
| US6194406B1 (en) | 1995-12-20 | 2001-02-27 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic disease |
| US5922737A (en) * | 1996-02-21 | 1999-07-13 | Hoechst Marion Roussel, Inc. | Substituted N-methyl-N-(4-(4-(1H-Benzimidazol-2-YL-amino) piperidin-1-YL)-2-(arlyl) butyl) benzamides useful for the treatment of allergic diseases |
| US5932571A (en) * | 1996-02-21 | 1999-08-03 | Hoechst Marion Roussel, Inc. | Substituted N-methyl-N-(4-(4-(1H-benzimidazol-2-yl) {1,4}diazepan-1-yl)-2-(aryl) butyl) benzamides useful for the treatment of allergic diseases |
| US5998439A (en) * | 1996-02-21 | 1999-12-07 | Hoescht Marion Roussel, Inc. | Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides useful for the treatment of allergic diseases |
| ES2124167B1 (en) * | 1996-06-04 | 1999-09-16 | Espanola Prod Quimicos | NEW DERIVATIVES OF BENZMIDAZOLE WITH ANTIHISTAMINE ACTIVITY. |
| KR100494448B1 (en) * | 1996-06-04 | 2005-12-02 | 화브리까 에스파놀라 데 프로둑또스 뀌미꼬스 이 화르마세우띠꼬스 쏘시에떼 아노님 | Novel benzoimidazole derivatives with antihistamine activity |
| US6136807A (en) * | 1998-11-10 | 2000-10-24 | 3M Innovative Properties Company | Composition for the transdermal delivery of lerisetron |
| TWI225488B (en) * | 1999-12-21 | 2004-12-21 | Janssen Pharmaceutica Nv | Derivatives of homopiperidinyl substituted benzimidazole analogues |
| NZ535763A (en) * | 2002-04-18 | 2007-06-29 | Schering Corp | (1-4-piperidinyl) benzimidazole derivatives useful as histamine H3 antagonists |
| US7105505B2 (en) | 2002-04-18 | 2006-09-12 | Schering Corporation | Benzimidazole derivatives useful as histamine H3 antagonists |
| JP4355917B2 (en) | 2003-10-29 | 2009-11-04 | 信越化学工業株式会社 | Nitrogen-containing organic compound, resist material, and pattern forming method |
| JP5629214B2 (en) * | 2008-02-12 | 2014-11-19 | ユーハン・コーポレイションＹＵＨＡＮ Ｃｏｒｐｏｒａｔｉｏｎ | Process for producing 2-methyl-2'-phenylpropionic acid derivative and novel intermediate compound used therefor |
| ES2612934T3 (en) * | 2011-09-26 | 2017-05-19 | Merck Patent Gmbh | Piperidin benzyl compounds as a lysophosphatidic acid receptor (LPA) antagonist |
| CN102675101B (en) * | 2012-05-16 | 2014-01-29 | 王蕾 | Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine |
| EP3040334A1 (en) * | 2014-12-29 | 2016-07-06 | Faes Farma, S.A. | New benzimidazole derivatives as antihistamine agents |
| CN106146308A (en) * | 2015-04-09 | 2016-11-23 | 南京长澳医药科技有限公司 | Alpha, alpha-dimethyl-4-(2-halogen acetyl group) purification process of phenylacetate |
| EP3170817A1 (en) | 2015-11-20 | 2017-05-24 | Faes Farma, S.A. | Co-crystals of benzimidazole compounds |
| EP3170816A1 (en) | 2015-11-20 | 2017-05-24 | Faes Farma, S.A. | Supersaturated compositions of benzimidazole compounds |
| LT3681475T (en) | 2017-10-16 | 2021-02-25 | Faes Farma, S.A. | Aqueous compositions comprising bilastine and mometasone |
| AU2019209214B2 (en) | 2018-01-18 | 2023-11-23 | Faes Farma, S.A. | Ophthalmic compositions comprising bilastine, a beta-cyclodextrin and at least one gelling agent |
| EP3725298A1 (en) | 2019-04-16 | 2020-10-21 | Faes Farma, S.A. | Stable and preserved pharmaceutical compositions of bilastine |
| EP4188339A1 (en) | 2020-07-30 | 2023-06-07 | Faes Farma, S.A. | Decongestant drug delivery system |
| WO2023156559A1 (en) | 2022-02-17 | 2023-08-24 | Faes Farma, S.A. | Bilastine composition for once-daily parenteral administration |
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| JPS5879983A (en) * | 1981-11-06 | 1983-05-13 | Kanebo Ltd | Novel benzimidazole derivative, its preparation and pharmaceutical composition thereof |
| PH23995A (en) * | 1984-01-09 | 1990-02-09 | Janssen Pharmaceutica Nv | 4((bicycle heterocyclyl)-methyl and hetero)piperidines |
| SE8505112D0 (en) * | 1985-10-29 | 1985-10-29 | Haessle Ab | NOVEL PHARMACOLOGICAL COMPOUNDS |
| ES8604934A1 (en) * | 1985-11-19 | 1986-03-01 | Inke Sa | Fluoro:phenyl-methyl piperidinyl benzimidazole-2-amine prepn. |
| US5215974A (en) * | 1986-11-21 | 1993-06-01 | Aktiebolaget Hassle | Certain pyridyl[(methylthio- or methyl sulfinyl)-2 benzimidazol-2-yl]N-methyl phosphonates useful for treating gastric-acid secretion related diseases |
| US4988689A (en) * | 1987-07-01 | 1991-01-29 | Janssen Pharmaceutica N.V. | ((Pharmacologically active bicyclic heterocyclic)methyl and -heteroatom) substituted hexahydro-1H-azepines and pyrrolidines |
| NZ238863A (en) * | 1990-07-19 | 1993-03-26 | Janssen Pharmaceutica Nv | Substituted thiazolyl and pyridinyl derivatives |
| FR2668150B1 (en) * | 1990-10-17 | 1994-11-18 | Theramex | NOVEL DERIVATIVES OF TERBUTYLPHENYL 1-AMINO 4-HYDROXYBUTANE, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
-
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- 1992-07-20 ES ES09201512A patent/ES2048109B1/en not_active Expired - Lifetime
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- 1993-07-16 EP EP93500105A patent/EP0580541B1/en not_active Expired - Lifetime
- 1993-07-16 DE DE69326650T patent/DE69326650T2/en not_active Expired - Fee Related
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| Publication number | Publication date |
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| AU667920B2 (en) | 1996-04-18 |
| NO303014B1 (en) | 1998-05-18 |
| ATE185344T1 (en) | 1999-10-15 |
| EP0580541A1 (en) | 1994-01-26 |
| CA2100503A1 (en) | 1994-01-21 |
| TW225529B (en) | 1994-06-21 |
| JPH07291964A (en) | 1995-11-07 |
| KR940005609A (en) | 1994-03-21 |
| MX9304215A (en) | 1994-02-28 |
| ES2048109B1 (en) | 1994-12-16 |
| NO932607D0 (en) | 1993-07-19 |
| DE69326650D1 (en) | 1999-11-11 |
| NO932607L (en) | 1994-01-21 |
| DE69326650T2 (en) | 2000-06-08 |
| ES2048109A1 (en) | 1994-03-01 |
| US5322850A (en) | 1994-06-21 |
| EP0580541B1 (en) | 1999-10-06 |
| ZA935195B (en) | 1994-09-19 |
| AU4194693A (en) | 1994-01-27 |
| FI933213A0 (en) | 1993-07-15 |
| FI933213A (en) | 1994-01-21 |
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